The document summarizes different types of insulin, including human insulin and newer insulin analogues. It describes the structure and production of human insulin and discusses problems with conventional insulins like regular insulin. It then provides details on various short-acting and long-acting insulin analogues like insulin lispro, insulin glargine, insulin detemir, and insulin degludec, including their structures, mechanisms of action, advantages over human insulin, dosing, and pregnancy categories. The document also briefly mentions other newer insulins under development or approval like inhaled insulin and insulin fusion proteins.

1. NEWER INSULIN
Sanjay Singh
Moderator: Dr. Prabhat Agarwal

4. HUMAN INSULIN
• Insulin is a 51-amino acid peptide hormone comprising two
polypeptide chains, the A and B chains,which are linked by
disulphide bridge.
• Insulin is synthesized on the ribosomes of the rough
endoplasmic reticulum (RER) as a single amino acid chain
precursor molecule called preproinsulin
• After removal of the signal peptide, proinsulin is
transferred from the RER to the Golgi apparatus, where
soluble zinc-containing proinsulin hexamers are formed.
The prohormone convertase enzyme,
• PC1/3, finally acts outside the Golgi apparatus to produce
the mature insulin and connecting peptide (C-peptide).
harrisons 19th edition

5. • In the pancreatic islet, both insulin and C-peptide
are released simultaneously in equimolar
quantities by exocytosis in response to a number
of stimuli, including glucose and amino acids.
• Proinsulin contains 86 amino acids, while insulin
has 21 amino acids in the A chain and 30 in the B
chain.
• One unit insulin is defined as the amount of
insulin that will lower the blood glucose of the
healthy 2kg rabbit that has fasted for 24 hours to
45mg/dl within 5 hrs*.
harrisons 19 edition

6. secretion
• In response to nutrients following a meal, insulin is
secreted in a coordinated pulsatile fashion from the
β-cells into the portal vein in a characteristic biphasic
Pattern
• first there is an acute rapid ‘first phase’ release of
insulin, lasting for a few minutes
• followed by a less intense more sustained ‘second
phase’.
• Pancreatic β-cells also secrete 0.25–1.5 units of
insulin/h during the fasting state. Although at a low-
level, this background secretion accounts for over
50% of total daily insulin Production.
harrisons 19th edition

8. • The older commercial preparations were
produced from beef and pork pancreas.
• They contained about 1% of other protein
(proinsulin, polypeptides, pancreatic proteins,
insulin derivatives etc.) which were potentially
antigenic.
• They are no longer produced and have been
replaced by highly purified pork/beef insulin,
recombinant human insulin and insulin
analogues.
• From the ESSENTIALS OF PHARMACOLOGY 7TH EDITION K.D TRIPATHI

9. Problems with conventional insulins
• Normally, insulin concentration peaks at 30-45 minutes after a meal
and returns to basal level after 2-3 hrs.
• The onset of action of regular insulin is too slow, its action peaks at
1-2 hrs after an injection and the duration of action is too long i.e. 6
hrs.
• This leads to post prandial hyperglycemia and late hypoglycemia.
• It is therefore, recommended to administer regular human insulin
30-45 minutes before meals, which restricts patient lifestyle and
compliance .
• Similarly the available intermediate or long acting insulin
preparation are unable to provide continuous basal insulin for 24
hrs.
• This causes premeal and fasting hyperglycemia and night
hypoglycemia .
From the Department of Pharmacology, Christian Medical College and Hospital, Ludhiana,141008, India.
Correspondence to : Dr. Dinesh.K. Badyal, Head, Department of Pharmacology CMC, Ludhiana India.
REVIEW ARTICLE
Jasleen Kaur, Dinesh K. Badyal

12. Advantages of Insulin Analogues
1. They provide better control of sugars
2. They carry low risk of hypoglycemia Particularly
nocturnal hypoglycemia
3. They do not have to be injected half an hour before
meals
4. Compliance is improved with long acting analogues as
once a day the insulin
5. The need for snacks between meal may be reduced with
short acting analogues
6. Advantage in term of weight gain epically with detemir
insulin.
From the Department of Pharmacology, Christian Medical College and Hospital, Ludhiana,141008, India. Correspondence to : Dr. Dinesh.K. Badyal, Head,
Department of Pharmacology CMC, Ludhiana India.
REVIEW ARTICLE
Jasleen Kaur, Dinesh K. Badyal

13. NEWER INSULINS
• Novel short or long acting insulin analogues also
called ‘designer insulin’.
• The B chain 26-30 region is critical for insulin
receptor recognition and has been the site
preferred for structural alteration with the aim to
modify the pharmacokinetic profile of insulin
molecule.
• Major concern of all insulin analogues is their
altered mitogenic properties and risk of
carcinogenicity on long term.

14. Newer insulins
Insulins Date of approval indications
Insulin lispro (Humalog)
(mrp 410 ; 10 ml)
June 14, 1996 In type I and type II
diabetes mellitus along
with long acting insulin
Insulin aspart (Novolog)
(mrp 560; 3 ml)
June 07, 2000 In Type I and II adult DM
along long acting insulin &
in insulin pumps
Insulin glulisine (Apidra) April 26, 2004 In Type I and II adult DM
and in insulin pumps
Insulin glargine (Lantus)
(2400;1400)
April 20, 2000 In Type I and II DM
Insulin detemir(Levemir)
Insulin degludec(tresiba)
June16, 2005
Sep.2015
In Type I
Inhaled Insulin (Exubera)
Inhaled Insulin (Afrezza)
June27, 2007
June 2014
Type I DM as add onto
long acting
Type II DM alone or along
with oral antidiabetics or
long acting insulin

15. Insulin Preparations
Short acting:
• These have rapid onset and shorter duration of
action.
• The peak of onset corresponds more closely
with the post prandial peak.
• The shorter duration of action prevents the
incidence of hypoglycemia.

16. A. Lispro insulin
• first recommended DNA analogue.
• structurally modified human recombinant insulin
• inversion of proline at position 28 with lysine at position 29.
• change eliminates the ability to dimerize results in faster
absorption rates
• administer 0 - 15 min pre-meal vs. 30 - 45 min
• peak action in 0.5 - 1 h vs. 1.5 - 2 h.
• Insulin lispro has been tested for use in pregnancy and
gestational diabetes.
• It was found to be as effective as regular insulin and no
teratogenic effects were found

18. B.Insulin Aspart
• Substitution of proline at 28 position with aspartic
acid.
• This analogue also prevents the formation of
hexamers leading to rapid absorption from
subcutaneous tissue than soluble insulin
• It has similar binding properties and mitogenecity
characteristics as regular human insulin and has
equivalent immunogenecity.
• Pregnancy cat B

21. C.Insulin Glulisine
• Substitution of asparagine at position B3 by
lysine and lysine at position B 29 by glutamine.
• It exerts its action by causing insulin receptor
substrate-2 (IRS-2) phosphorylation and also
has antiapoptotic activity against cytokine and
fatty acid induced â-cell destruction.
• Due to antiapoptotic activity, it counteracts
autoimmune and lipotoxicity induced â-cell
destruction.
• But insulin glulisine carry the risk of
tumorogenecity due to increased binding to
IGF-1 receptor and increases mitogenic activity
• early trial results indicate less “clumping” - may
be insulin of choice
• Pregnancy cat C

24. LONG ACTING ANALOGUES :
Ideal basal insulin has long duration of action and provide 24 hour control
with minimum variation in absorption and has to be given once a day.
A.Insulin Glargine
• It was the first long acting basal human insulin available in the market.
• The structure was designed by substituting an asparagine residue with a
glycine at position 21 of the A-chain and elongating the B-chain at the C-
terminus by addition of 2 arginine residues
• Modification of B-chain caused the pH to shift from 5.4 to 6.7 and makes
it less soluble at physiological pH and more soluble at acidic pH. The
glycine substitution of A chain of insulin glargine stabilizes the hexamer
structure and therefore, contributing to delayed delivery from
subcutaneous depot and maintaining its stability in acidic solution.
• Insulin glargine is not to be mixed with other insulin, as it becomes cloudy
and results in alteration of pharmacokinetic and pharmacodynamics
profile.

25. • It precipitates at physiological pH and absorbs slowly
from injection site. Therefore, provides basal insulin
that mimic insulin profile of healthy individual.
• It has slow onset of action and achieves a maximum
effect after 4-6 hrs and this activity is maintained for
11-24 hours or longer.
• Insulin glargine has more affinity to the insulin growth
factor 1 receptor (IGF- 1),therefore has increased
mitogenic potency compared to human insulin in in-
vitro studies.
• Pregnancy cat C

27. Initial dose
• Type 1 DM: Starting dose should be approx one
third of the total daily insulin requirement.
• Short acting premeal insulin should be used to
satisfy the remaining two thirds of the daily
insulin requirements.
• Insulin glargine should be used in combination
with a short acting or rapid-acting insulin.
• Usual daily maintenence range is 0.5-1
unit/kg/day.

28. • Type2 DM: starting dose who are not
currently treated with insulin is 10 units (or
0.2 unit/kg) once daily.

29. Dosing considerations
• Indicates for once daily SC administrations; exhibits
relatively constant glucose-lowering profile over 24
hrs.
• May be administered at any time during a day; should
be administered SC only daily at the time every day.
• As with all insulins, injection sites should be rotated
within the same region to reduce the risk of
lipodystrophy.
• No clinical difference in insulin glargine absorption
after abdominal, deltoid, or thigh SC administration.

30. Converting from other insulin
• If changing from a t/t regimen with an
intermediate or long acting insulin to a regimen
with insulin glargine, the amount and timing of
shorter acting insulins and doses of any oral
antidiabitics may need to be adjusted.
• From once daily NPH insulin to once daily insulin
glargine: initial dose is the same as the dose of
NPH that is being discontinued.
• From twice daily NPH insulin to once daily
insulin glargine: initial dose is 80% of the total
daily NPH dose that is being discontinued.

31. B. INSULIN DETEMIR
• Modifying insulin by binding to serum protein albumin
prolongs the duration of action.
• It is a soluble basal insulin analogue at neutral pH.
• It is created in which amino acid threonine at B 30 is
removed and acetylated with a 14-C fatty acid chain to
lysine B29 which causes it to bind reversibly to
albumin in plasma.
• Only free insulin detemir is biologically active and its
slow dissociation from albumin results in delayed
action.

32. • Its onset of action takes 1-2 hours and duration of
action is for 24 hours.
• It is given twice daily to obtain a smooth basal insulin
level.
• Reduction in body weight is another advantage which
may be due to direct effect on hypothalamus.
• But its lower affinity for insulin receptor necessitates
higher doses compared to human insulin.
• It has low insulin receptor binding affinity and
metabolic potency so it is less potent in binding to IGF-
1R & stimulating mitogenesis. Therefore, it has reduced
risk of inducing tumours

34. Dosing
• Once daily dosage: administer SC with
morning meal or at bedtime.
• Twice daily dosage: administer SC with
morning meal and either with evening meal,
at bedtime or 12 hr after the morning dose.

35. Initial dose
• Type 1 DM: approx one third of the total daily
insulin requirement SC; rapid acting or short
acting, premeal insulin should be used to
satisfy the remainder of the daily insulin
requirements; usual daily maintenance range
is 0.4-0.6 unit/kg/day.
• Type2 DM: inadequately controlled on oral
medication 10 units/day SC (or 0.1-0.2
unit/day) in evening or divided dose.

36. Conversion from other insulins
• If conversion from insulin glargine: change can
be accomplished on a unit to unit basis.
• If converting from NPH insulin: change may be
accomplished on a unit to unit basis; however,
some patients with type 2 diabetes may
require more insulin detemir than NPH insulin.

37. Dosing considerations
Dose adjustments:
• Look for consistent pattern in blood sugars for
>3 days.
• Same time each day: compare blood glucose
level with previous levels that time of day
• Consider eating and activity patterns during
the day.

38. Rate of dose adjustments:
• Adjust only 1 insulin dose at a time
• Correct hypoglycemia 1st.
• Correct highest blood sugar next.
• If all blood sugars are high: correct morning
fasting blood glucose 1st .
• Change insulin doses in small increments: Type1
diabetes 1-2 unit change; Type 2 diabetes
resistant to diet and exercise 2-3 change.

41. INSULIN DEGLUDEC
• Insulin degludec (INN/USAN) is an ultralong-acting basal insulin
analogue that was developed by Novo Nordisk under the brand
name Tresiba.
• Insulin degludec is a modified insulin that has one single amino acid
deleted in comparison to human insulin, and is conjugated to
hexadecanedioic acid via gamma-L-glutamyl spacer at the amino
acid lysine at position B29.
• It is administered via subcutaneous injection once daily to help
control the blood sugar level of those with diabetes.
• It has a duration of action that lasts up to 40 hours (compared to 18
to 26 hours provided by other marketed long-acting insulins such as
insulin glargine and insulin detemir), which would allow for a two or
three times weekly administration.
Marketing Authorisation Holder and Manufacturer Novo Nordisk A/S Novo Allé DK-2880 Bagsværd,
Denmark

52. INSULIN RYZODEG
• Ryzodeg is a soluble insulin product
consisting of the basal insulin degludec and
the rapid-acting prandial insulin aspart.
• Ryzodeg can be administered once- or twice-
daily with the main meal(s).

53. OTHER NEWER INSULIN
Albulin
• It is the newest insulin analogues which is developed and
reported by Duttaroy et al, in 2005.
• It is a single chain analogue produced in yeast or
mammalian cell.
• It consists of B and A chain of human chain linked by a
dodecapeptide linker and fused to NH(2) terminal of native
human serum albumin. It has been shown in various
studies that it has lower affinity to bind to insulin receptors.
• Albulin displays characteristics of a potent long- acting
insulin analog that can be evaluated for use as a novel
insulin therapy for patients with insulin-dependent
diabetes.
Diabetes. 2005 Jan;54(1):251-8.
Development of a long-acting insulin analog using albumin fusion technology.
Duttaroy A1, Kanakaraj P, Osborn BL, Schneider H, Pickeral OK, Chen C, Zhang G, Kaithamana S, Singh M, Schulingkamp R, Crossan D, Bock
J, Kaufman TE,Reavey P, Carey-Barber M, Krishnan SR, Garcia A, Murphy K, Siskind JK, McLean MA, Cheng S, Ruben S, Birse CE, Blondel O.

54. Inhaled Insulin
• By pulmonary route drugs have faster onset of action, even faster
than i.v. route and large surface area of lungs causes more
systemic absorption.
• If long-term safety and efficacy is confirmed, inhalation will
become the first non-subcutaneous route of insulin administration
for widespread clinical use.
• Exubera is first inhalational drug to be approved by FDA on Jan
2006.
• Exubera is an insulin product for pulmonary delivery in powder
form.
• Bioavailability is just 10% compared to regular human insulin given
by subcutaneous route with duration of action of 5-10 hours.
• Therefore, high doses of insulin have to be given about 8 times
the subcutaneous route to achieve glycemic control. The major
problems are loss of drug with inhaler and mouth during
inhalation, variation in absorption due to age related difference,
respiratory tract infection and smoking.
• Other side effects are mild to moderate cough, shortness of
breath, sore throat and dry mouth.

55. Enteral insulin:
There are two technologies used to obtain enteral
insulin.
Emishere technologies
It uses carriers to enable insulin resorption through
membranes. After resorption the carrier seperates from
insulin.
Nobotex
It has developed technology based on attachment of
amphophilic oligomers to insulin resulting in resistance
to enzymatic degradation. Insulin is absorbed into portal
circulation, reaching high concentration in liver, which
better mimics physiological secretion.
FROM B.NOVAK, Z. METELKO / NEW TRENDS IN INSULIN THERAPY

56. Orally absorbed insulin(oralin)
Generex has developing a aerosol containing insulin for buccal absorption , using an
applicator similar to those used in asthma medications.
Transdermal insulins
• Altea has developed trandermal patches for insulin delivery.
• The electronic adhesive patch is first applied to the skin , vaporizing superficial
dermal cells and forming micropores for insulin to pass through, and then insulin
patch is applied.
• It provide basal insulin delivery for 12 hrs.
• Idea has developed Transferosulin , using particles called transformers.
• Transformers are similar to lyposomes but are more deformable and can easier
pass through the skin.
• Their membranes contain phospholipids and has hydrophilic core inside where
insulin is carried.
FROM B.NOVAK, Z. METELKO / NEW TRENDS IN INSULIN THERAPY

57. Other Routes
• Pancreatic transplantation has also been tried but this
will remain limited to those patients receiving a kidney
transplant and immunotherapy.
• Islet cell transplantation is at an early though
encouraging stage following the availability of new less
toxic immunosuppressive agents .
• Artificial pancreas
1. Medronic minimed(part of Medtronic Inc.) presented
initial results of artificial beta cell prototype studies
at the 62nd scientific sessions of ADA.
2. It is a closed loop device consisting of implantable
peritoneal insulin pump and glucose sensor
implanted in the vena cava superior.

58. Insulin Delivery Devices
• Insulin syringes
• External Insulin Pumps
• Implantable Insulin Pumps
• Insulin Pens
• Insulin Injection Aids
• Insulin Jet Injectors
• Insulin Inhalers

60. FlexPen®
SoloStar® (sanofi aventis)
Examples of Insulin Pens
Pre-filled (Disposable)
Re-usable (uses insulin cartridges)
NovoPen® 4
HumaPen®

61. Portable Pen Injector

62. Inhalation device or insulin

63. Insulin administration
Sites
• Abdomen (fastest absorption & most
preferred)
• Buttocks
• Upper arm
• Thigh-lateral & anterior aspects (slowest)
• Rotate the site of injection around a
selected area
(Intermediate)

65. Types of insulin
Type of Insulin
& Brand Names
Onset Peak Duration
Role in Blood Sugar
Management
Rapid-Acting
Lispro 15-30 min. 30-90 min 3-5 hours Covers insulin needs for
meals eaten at the same
time as the injection.Aspart 10-20 min. 40-50 min. 3-5 hours
Glulisine 20-30 min. 30-90 min. 1-2½ hours
Short-Acting
Regular
30 min- 60
min
2-5 hours 5-8 hours
Covers insulin needs for
meals eaten within 30-60
minutes
Intermediate-Acting
NPH (N) 1-2 hours 4-12 hours 18-24 hours
Covers insulin needs for
about half the day or
overnight.

66. Types of insulin
Name of
Insulin
Onset Duration
Role in Blood
Sugar
Management
Long-Acting
Long-acting
insulin covers
insulin needs
for about one
full day.
Degludec 30-90 min No peak:
insulin is
delivered at
a steady
level.
Longer than 24
hours
Glargine 30-90 min Up to 24 hours
Detemir 1-120 min 20-24 hours

67. Types of insulin
Type of Insulin Onset Peak Duration
Role in Blood Sugar
Management
Pre-Mixed*
30/70 30 min. 2-4 hours 14-24 hours These products are
generally taken two
or three times a day
before mealtime.
50/50 30 min. 2-5 hours 18-24 hours
25/75 15 min.
30 min.-2½
hours
16-20 hours
Inhaler
Exubera Banned
Afrezza With in min 12 to 15 min 2-3 hours Post prandial effects.
*Premixed insulins are a combination of specific proportions of intermediate-
acting and short-acting insulin in one bottle or insulin pen (the numbers the brand
name indicate the percentage of each type of insulin).

68. Thank you
Thanks to all